The key pathologic event leading to the development of several disease entities, involves infiltration of the tissues with inflammatory cells - particularly neutrophils. Although the inflammatory reaction protects the organism and promotes tissue repair and healing, deleterious effects result if the mechanisms that regulate the response are altered. The clinical outcomes, therefore, of many disease states with an inflammatory component, including asthma, arthritis, diabetes and myocardial ischemia, are in many respects dependent on the extent that leukocytes are allowed to accumulate at those sites of inflammation and cause tissue destruction. It is therefore highly relevant that a clear understanding of the molecular mechanisms regulating leukocyte trafficking to and from the vasculature, be delineated so that scientists may rationally develop novel and effective therapies. Only recently have some of the molecular links between coagulation and inflammatory systems been established. In that respect, we have determined that thrombomodulin (TM), a critical cofactor in a natural anticoagulant pathway, has direct anti-inflammatory properties, and that lack of its lectin-like domain in mice results in a pro-inflammatory state, with augmented neutrophil extravasation and worse outcomes in models of arthritis, lung inflammation and myocardial ischemia. The goal of this proposal is to utilize a combination of biochemical techniques and mouse models of inflammation to evaluate the mechanisms by which TM exerts its anti-inflammatory properties. Specifically, we will focus on evaluating the role of TM in arthritis and myocardial ischemia, both of which are common disorders, lacking in fully adequate therapies. The mouse models representing these diseases are amenable to pharmacologic intervention, such that the effects of introducing recombinant forms of solubleTM - shown to prevent neutrophil adhesion - may be evaluated for their potency in modulating the inflammatory response. The results of the studies, to be tested in an excellent environment, will hopefully provide new insights that will lead to the design of more effective therapeutic approaches for inflammatory disease.